Review Article Compound Danshen Dripping Pill for Treating Nonproliferative Diabetic Retinopathy: A Meta-Analysis of 13 Randomized Controlled Trials

Hindawi Evidence-Based Complementary and Alternative Medicine Volume 2017, Article ID 4848076, 10 pages https://doi.org/10.1155/2017/4848076 Review Article Compound Danshen Dripping Pill for Treating Nonproliferative Diabetic Retinopathy: A Meta-Analysis of 13 Randomized Controlled Trials Wenjing Huang, 1,2 Qi Bao, 1,2 De Jin, 1,2 and Fengmei Lian 1 1 Department of Endocrinology, Guang anmen Hospital, China Academy of Chinese Medical Sciences, Beixiange 5, Xicheng District, Beijing 100053, China 2 China Academy of Chinese Medical Sciences, Beixiange 5, Xicheng District, Beijing 100700, China Correspondence should be addressed to Fengmei Lian; lfm565@sohu.com Received 4 December 2016; Revised 12 February 2017; Accepted 23 April 2017; Published 24 August 2017 Academic Editor: Mona Abdel-Tawab Copyright 2017 Wenjing Huang et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Objective. We assess the clinical effect of compound Danshen dripping pill (CDDP) for treating diabetic retinopathy (DR). Methods. Electronic databases were searched from January 2001 to October 2016 to locate randomized controlled trials (RCTs). Efficacy was measured as main outcome and s, hemorrhage, exudate, vision, and fundus fluorescein angiography (FFA) were measured as second outcomes. Methodological quality for each study was evaluated, RevMan 5 software was used to assess treatment effects, and GRADE was used to rate quality of evidence. Results. We located 13 RCTs and methodological quality was evaluated as high risk. Statistics indicated CDDP for treating DR was better than controls and DR risk was reduced 64% with CDDP (RR: 0.36, P = 0.68); retinal s (MD = 4.32NO, P < 0.00001); retinal hemorrhages (MD = 0.70PD, P = 0.03); exudate improvements (MD = 0.09PD, P = 0.79); visual changes (MD = 0.12 letter, P = 0.006); FFA (RR: 0.40, P = 0.003). About GRADE, quality of evidence was low. Conclusion. CDDP may be safe and efficacious for treating or delaying DR and may improve vision or delay vision loss. 1. Introduction Diabetic retinopathy (DR) is a major microvascular complication of diabetes that can lead to retinal detachment and blindness. Annually, 10 12% of new cases of blindness are attributed to DR and in Holland, as many as 21% of newly diagnosed blindness is due to DR [1 3]. One-quarter of DR patients develop severe visual impairment, attributed to diabetic macular edema and proliferative diabetic retinopathy (PDR) [4]. Once proliferation begins, it causes irreversible visual impairment. Blindness for diabetics in China is 25 times more frequent than in nondiabetics [5, 6] and about 20 million diabetics reside in China now, constituting the second largest diabetes population worldwide [7]. Therefore, preventing DR and reducing diabetic-induced visual impairment are key concerns. DR treatment includes systemic therapy to control glucose,bloodpressure,andserumlipidsaswellasoculardrugs. Severe nonproliferative diabetic retinopathy (NPDR) and PDRhavebeentreatedwithlasertherapy,whichprevented vision impairment and loss but did not improve visual acuity. Also, laser treatment may reduce visual field. For NPDR, drug intervention can delay progression of DR, improve visual function, and reduce side effects of laser treatment. Thus, the ability to predict progression in early stages of DR and drug intervention are important for reducing the risk of DR. At this time, no effective treatment for DR exists and nothing has been shown to slow or reverse visual impairment. The pathogenesis of DR is thought to be poor circulation which damages collateral eye vessels [8], so improved circulation is a therapeutic strategy. The herb Salvia miltiorrhiza (Danshen dripping pill, CDDP) was tested in American FDAII clinical trials for safety and efficacy for treating cardiovascular conditions such as myocardial infarction [9]. Also,CDDPisbeingstudiedtotreatDR[10],althoughthe data quality was poor and safety was not confirmed. Thus,

2 Evidence-Based Complementary and Alternative Medicine we performed a meta-analysis of randomized clinical trials (RCTs) to compare CDDP and placebo or approved therapies to assess any curative effect and safety of this drug. 2. Methods 2.1. Data Sources and Search Strategy. We searched the Chinese National Knowledge Infrastructure (CNKI), Chinese Scientific Journal Database (VIP), Chinese Biomedical Literature Database (CBM), WanFang Databases, PubMed, Medline, and Cochrane Library. We used these keywords: ( diabetic retinopathy OR diabetic eye diseases ) AND ( compound danshen dripping pill OR a danshen-containing Chinese herbal medicine ) AND ( randomized controlled trial OR controlled clinical trial OR random OR randomly OR randomized OR control ). We searched all articles published from January 2001 to October 2016. 2.2. Selection of Studies. Randomized controlled trials (RCTs) were selected which included CDDP as the main intervention and this was compared to approved therapy or controls. The primary outcome was efficacy and secondary outcomes were s, hemorrhage, exudate, vision, and FFA. Study participants were diagnosed with DR. Medical record reviews, retrospective studies, repeated reports of research studies, and animal experiments were excluded. 2.3. Data Extraction and Quality Assessment. Two authors independently extracted data (W. J. Huang and F. M. Lian) such as author, year of and country, sample size, age, sex, intervention (components of intervention), intervention details, dose, treatment duration, changes in s, hemorrhage, exudate, visual acuity, and FFA. For incomplete and suspicious data, authors were contacted by e-mail or phoned to obtain the information, but no author offered information. Disagreements over study eligibility were resolved with discussion with a third reviewer (Q. Bao). The Cochrane Handbook for Systematic Review was used to assess study quality [24]. Bias assessment criteria included adequate sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data addressed, being free of selective reporting, and being free of other es. We judged each item using three levels ( Yes means low risk of, No means high risk of, and Unclear means other es); see Table 2. 2.4. Data Analyses. Revman 5.0 software was used to analyze data, which was provided by the Cochrane Collaboration. The risk ratio (RR) for data was used as pooled statistics, and weighted mean difference (WMD) of measurement data was used as pooled statistics, and 95% confidence intervals (CI) were calculated [25]. Heterogeneity was assessed by WHAT test and I 2 > 50% or P < 0.1 wasusedtoassess significance, and a random effects model was used to explain possible causes of heterogeneity. If I 2 < 50%, there was no heterogeneity and a fixed effect model was used [26]. Publication was assessed using a funnel plot [27]. Studies found in initial research (n = 143) CNKI (n =50) WangFang (n = 70) VIP (n =21) PubMed (n =2) Records after duplicates removed (n =90) Records screened (n =40) Full-text articles assessed for eligibility (n =13) 3. Results Animal studies (n =3) Retrospective study (n =7) Not related to the subject (n =19) Noncontrolled clinical trials (n =21) Not meeting the inclusion criteria (n = 12) Meeting the exclusion criteria (n =3) Not finding full text and literature description and others (n =12) Figure 1: Flow chart of studies selection process. 3.1. Study Characteristics. 143 studies were initially identified; finally, 13 studies [11 22] remained after eliminating duplications, examining titles and abstracts, and reviewing full texts. Figure 1 depicts trial selection and number of studies found. The 13 studies included 874 participants, 477 males and 397 females. Of these, 448 were participants in the intervention group, and 426 were controls. All participants were inpatients/outpatients of the Endocrine Department andtheywereaged30to80years.diagnosticcriteriaof the13studieswerebasedontheacceptedandauthoritative diagnostic criteria for DR [28 31]. In intervention group, 10 studies [11, 13 15, 17 20, 22, 23] used CDDP alone, and 3 studies [12, 16, 21] used CDDP plus conventional drugs. In control group, 2 studies [20, 21] used placebo, 4 studies [11, 13 15] used vitamin B1 and/or LuDing tablets and/or PanShengDing tablets and/or inosine tablets, and 7 studies [16 22]usedcalciumdobesilate.Thefollow-upperiodranged from 2 to 6 months, and selected studies are summarized in Table 1. 3.2. Quality Assessment. Quality assessments are summarized in Table 2. Only 1 study described methods adequately [23]. The table addresses the remaining study deficits. No

Evidence-Based Complementary and Alternative Medicine 3 Trials Qi et al. 2007 [11] He and Zheng 2013 [12] Xu 2011 [13] Zhon et al. 2008 [14] Liu and Hao 2011 [15] Meng et al. 2011 [16] Chen and Zhon 2006 [17] Zhou 2008 [18] Wang et al. 2016 [19] Sample (N) 42 (23/19) 84 (42/42) 80 (40/40) 64 (34/30) 52 (26/26) 58 (30/28) 63 (31/32) 46 (28/18) 90 (45/45) 58 Jin et al. 2009 [20] (30/28) Shi 2010 [21] Luo et al. 2015 [22] Lian et al. 2015 [23] 68 (35/33) 57 (28/29) 112 (56/56) Table 1: Characteristics of included RCTs. Male : female Age (years) Experimental Control 25 : 17 36 72 CDDP Vitamin B1 + LuDing tablets Duration (months) 48 : 36 32 70 CDDP Placebo 2 39 : 41 38 : 26 52.3 54.5 32 72 34 74 CDDP 30 : 22 39 76 CDDP 39 : 19 32 : 31 23:23 47 : 43 31 : 27 50.60 ± 8.70 51.20 ± 7.90 54.60 ± 10.40 58.12 ± 9.31 50.40 ± 8.70 50.50 ± 9.36 47 77 48 76 62.78 ± 7.69 61.11 ± 7.27 36 : 32 38 76 37 : 20 52 : 60 59.54 ± 7.46 57.8 ± 10.03 58.97 ± 7.6 58.97 ± 8.1 LuDing tablets + vitamin C + PanShengDing tablets CDDP LuDing tablets + vitamin C 3 CDDP + calcium dobesilate LuDing tablets + vitamin C + inosine tablets 3 3 3 Outcomes measured Visual acuity, hemorrhage, Visual, exudate, hemorrhage, Efficacy, Efficacy, FFA Visual acuity, hemorrhage, Calcium dobesilate 6 Efficacy CDDP Calcium dobesilate 3 Efficacy, visual acuity CDDP Calcium dobesilate 6 Efficacy CDDP Calcium dobesilate 2 CDDP Calcium dobesilate 3 CDDP + calcium dobesilate Efficacy, visual acuity, FFA Visual acuity, hemorrhage, Calcium dobesilate 3 Efficacy CDDP Calcium dobesilate 3 CDDP Placebo 6 Visual acuity, hemorrhage, Exudate, hemorrhage, FFA, study clearly described method of allocation concealment and blinding procedures. All studies showed the baseline data of the two groups were comparable, and quit and lost to follow-up cases and adverse events were not recorded. The methodological quality was assessed to be of high risk. 3.3. Effect of the Interventions 3.3.1. Efficacy. According to Guiding Principles of Clinical Research on Chinese Medicine Traditional and New Drugs, efficacy was assessed based on fundal improvements measured with ophthalmoscopy, fundus fluorescein angiography (FFA) to assess s, hemorrhage and exudate areas, and improved vision using a visual chart [28]. Efficacy was evaluated being significantly effective, effective, and ineffective. Total efficacy was evaluated based on significantly effective and effective data, and this was a chief overall outcome. Seven studies were examined [13, 16 19, 21, 23] and their data were homogenous and DR risk was reduced 64% by CDDP (RR: 0.36, Chi 2 =4.01,P = 0.68, I 2 =0%,95%CI[0.28 to 0.46], and P < 0.00001). Thus, a fixed effects model was used for statistical analysis and data showed that treatment groups fared significantly better than controls. To compare curative effects of treatment and controls, subgroup was used. Two studies [16, 21] used CDDP plus conventional drugs for treatment, and five studies [13, 17 19, 23] only used CDDP for treatment. Two kinds of studies suggested that treatment was better than controls (N = 126, RR: 0.27, 95% CI [0.13 to 0.59], Z = 3.33, and P = 0.0009 and N = 391, RR: 0.38, 95% CI [0.29 to 0.49], Z = 7.33, and P < 0.00001)andthesedataappearin Figure 2. 3.3.2. Microaneurysms. Five studies [11, 12, 15, 20, 22] reported participants who had more s (Chi 2 =2.50, P = 0.65, andi 2 =0%).Thus,fixedeffectsmodelwasused for statistical analysis. Microaneurysms were significantly improved in the treatment group compared with controls (N = 293, Z = 7.76, MD = 4.32, 95% CI [ 5.41 to 3.23], and P < 0.00001); see Figure 3. 3.3.3. Hemorrhages. Six studies [11, 12, 15, 20, 22, 23] provided data for improvements of retinal hemorrhages. Significant heterogeneity was found among these six studies (Chi 2 =

4 Evidence-Based Complementary and Alternative Medicine Studies Adequate sequence generation Allocation concealment Table 2: Quality assessment of enrolled RCTs. Blinding of participants and personnel Blinding of outcome assessment Incomplete outcome data addressed Free of selective reporting Free of other es Risk of Qi et al. 2007 [11] Unclear Unclear No Unclear Yes No Unclear High He and Zheng 2013 Unclear Unclear Unclear Unclear Yes No Unclear High [12] Xu 2011 [13] Unclear Unclear Unclear Unclear Yes No Unclear High Zhon et al. 2008 [14] Unclear Unclear Unclear Unclear No Yes Unclear High Liu and Hao 2011 [15] Unclear Unclear Unclear Unclear Yes No Unclear High Meng et al. 2011 [16] Unclear Unclear Unclear Unclear No Yes Unclear High Chen and Zhon 2006 Unclear Unclear Unclear Unclear No Yes Unclear High [17] Zhou 2008 [18] Unclear Unclear Unclear Unclear Yes No Unclear High Wang et al. 2016 [19] Unclear Unclear Unclear Unclear Yes No Unclear High Jin et al. 2009 [20] Unclear Unclear Unclear Unclear Yes No Unclear High Shi 2010 [21] Unclear Unclear No Unclear Yes No Unclear High Luo et al. 2015 [22] Unclear Unclear Unclear Unclear Yes No Unclear High Lian et al. 2015 [23] Yes Yes Yes Yes Yes Yes Yes Low 65.52, P < 0.00001, and I 2 = 92%). Using a random effects model, we confirmed a significant difference between treatments and controls (N = 405, Z = 2.14, MD= 0.70, 95% CI [ 0.76 to 0.03],andP = 0.03); see Figure 4. 3.3.4. Exudate. Two trials [12, 23] provided data for exudate, and they did not show homogeneity (Chi 2 =9.69,P = 0.002, and I 2 = 90%). A random effects model indicated that there were no significant differences between treatment groups and controls so there may have been differences in intervention measures, observation methods, or periods of intervention (N = 196, Z = 0.27, MD = 0.09, 95%CI[ 0.71 to 0.54], Z = 0.27,andP = 0.79); see Figure 5. 3.3.5. Visual. Five studies [11, 15, 17, 20, 22] reported data for visual acuity and significant heterogeneity was found (Chi 2 =14.35,P = 0.006, andi 2 = 72%). A random effects model indicated that there were significant differences between treatment groups and controls (N = 272, Z = 2.77, MD = 0.12,95%CI[ 0.21 to 0.07], Z = 2.77,andP = 0.006); see Figure 6. 3.3.6. Fundus Fluorescein Angiography (FFA). Three studies [18, 19, 23] provided data for fundal improvements and they did not show homogeneity (Chi 2 =5.99,P = 0.05, andi 2 = 67%). A random effects model indicated that treatment groups improved more than controls (N = 266, Z = 3.02, RR: 0.40, 95% CI [0.22 to 0.73], and P = 0.003); see Figure 7. 3.4. Publication Bias. An inverted funnel pattern analysis was used to confirm and the asymmetrical figure indicated potential that might influence results (Figure 8). Although we conducted comprehensive search to avoid, some negative results may not have been published. Study quality was not homogeneous, and most studies did not indicate randomization approaches. Other deficits may have compromised. Even so, included studies had definite diagnostic criteria, and baselines of treatment groups and controls were comparable. Thus, we conclude that CDDP improve fundal lesions of DR participants. 3.5. Result of GRADE. GRADE provides a clear and comprehensive methodology for rating the confidence in estimates (quality of evidence). It was used to evaluate effects of CDDP on DR and we confirmed a low quality of evidence. Better high-quality RCTs are needed to confirm the effect of CDDP, Table 3.

Evidence-Based Complementary and Alternative Medicine 5 Treatment Control Risk ratio Events Total Events Total M-H, fixed, 95% CI 1.1.1 CDDP + C versus C Shi 2010 Meng et al. 2011 3 4 35 30 11 13 33 28 8.1% 9.6% 0.26 [0.08, 0.84] 0.29 [0.11, 0.78] Subtotal (95% CI) 65 61 17.8% 0.27 [0.13, 0.59] Total events 7 24 Heterogeneity: 2 =0.02, df = 1 (P = 0.89); I 2 =0% Test for overall effect: Z=3.33(P = 0.0009) Risk ratio M-H, fixed, 95% CI 1.1.2 CDDP versus C Zhou 2008 4 28 8 18 7.0% 0.32 [0.11, 0.91] Hua 2011 13 40 35 40 25.1% 0.37 [0.23, 0.59] Wang et al. 2016 2 45 11 45 7.9% 0.18 [0.04, 0.77] Lian et al. 2015 23 56 50 56 35.9% 0.46 [0.33, 0.64] Chen and Zhon 2006 2 31 9 32 6.4% 0.23 [0.05, 0.98] Subtotal (95% CI) 200 191 82.2% 0.38 [0.29, 0.49] Total events 44 113 Heterogeneity: 2 = 2.95, df = 4 (P = 0.57); I 2 =0% Test for overall effect: Z=7.33(P < 0.00001) Total events Heterogeneity: 2 =4.01, df = 6 (P = 0.68); I 2 =0% Test for overall effect: Z = 8.05 (P < 0.00001) 51 Test for subgroup differences: not applicable 265 252 100.0% 137 0.36 [0.28, 0.46] 0.01 0.1 1 10 100 Figure 2: Comparison of efficacy of CDDP. Treatment Control Mean SD Total Mean SD Total IV, fixed, 95% CI Luo et al. 2015 21.14 18.57 28 21.88 15.49 29 1.5% 0.74 [ 9.63, 8.15] He and Zheng 2013 17.65 7.49 42 19.25 11.95 42 6.5% 1.60 [ 5.87, 2.67] Jin et al. 2009 10.2 3.1 30 14.9 3.3 28 43.7% 4.70 [ 6.35, 3.05] Liu and Hao 2011 10.5 5.21 26 14.6 5.4 26 14.3% 4.10 [ 6.98, 1.22] Qi et al. 2007 8.9 2.1 23 13.5 3.7 19 34.0% 4.60 [ 6.47, 2.73] IV, fixed, 95% CI 149 144 Heterogeneity: 2 =2.50, df = 4 (P = 0.65); I 2 =0% Test for overall effect: Z=7.76(P < 0.00001) 100.0% 4.32 [ 5.41, 3.23] 20 10 0 10 20 Figure 3: A comparison of the effectiveness of CDDP on retinal s improvement. Treatment Control Mean SD Total Mean SD Total Luo et al. 2015 0.14 0.52 28 0.15 0.46 29 16.9% 0.01 [ 0.27, 0.25] He and Zheng 2013 0.84 0.6 42 0.96 0.71 42 16.6% 0.12 [ 0.40, 0.16] Jin et al. 2009 1.6 0.4 30 2.4 0.6 28 16.8% 0.80 [ 1.06, 0.54] Lian et al. 2015 0.56 0.99 56 0.22 1.03 56 15.4% 0.34 [ 0.03, 0.71] Liu and Hao 2011 0.9 0.82 26 1.93 0.2 26 16.1% 1.03 [ 1.35, 0.71] Qi et al. 2007 0.6 0.2 23 1.3 0.2 19 18.1% 0.70 [ 0.82, 0.58] 205 200 Heterogeneity: 2 = 0.19; 2 = 65.52, df = 5 (P < 0.00001); I 2 = 92% Test for overall effect: Z=2.14(P = 0.03) 100.0% 0.40 [ 0.76, 0.03] 2 1 0 1 2 Figure 4: A comparison of the effectiveness of CDDP on hemorrhage improvement.

6 Evidence-Based Complementary and Alternative Medicine He and Zheng 2013 Lian et al. 2015 Treatment Control Mean SD Total Mean SD Total 0.85 0.57 42 1.26 0.81 42 49.5% 0.41 [ 0.71, 0.11] 0.31 0.91 56 0.08 0.48 56 50.5% 0.23 [ 0.04, 0.50] 98 98 Heterogeneity: 2 = 0.18; 2 = 9.69, df = 1 (P = 0.002); I 2 = 90% Test for overall effect: Z=0.27(P = 0.79) 100.0% 0.09 [ 0.71, 0.54] 2 1 0 1 2 Figure 5: A comparison of the effectiveness of CDDP on exudate improvement. Chen and Zhon 2006 Luo et al. 2015 Jin et al. 2009 Liu and Hao 2011 Qi et al. 2007 Control Treatment Mean SD Total Mean SD Total 4.73 0.18 32 4.86 0.16 31 22.4% 0.13 [ 0.21, 0.05] 0.17 0.72 0.61 0.63 0.18 29 0.14 0.17 28 0.15 28 0.91 0.16 30 0.22 26 0.78 0.25 26 0.23 19 0.79 0.25 23 21.6% 22.9% 17.4% 15.7% 0.03 [ 0.06, 0.12] 1.19 [ 0.27, 0.11] 0.17 [ 0.30, 0.04] 0.16 [ 0.31, 0.01] 134 138 Heterogeneity: 2 = 0.01; 2 = 14.35, df = 4 (P = 0.006); I 2 = 72% Test for overall effect: Z=2.77(P = 0.006) 100.0% 0.12 [ 0.21, 0.04] 1 0.5 0 0.5 1 Figure 6: CDDP efficacy for vision improvement. Lian et al. 2015 Wang et al. 2016 Zhon et al. 2008 Treatment Control Risk ratio Events Total Events Total M-H, random, 95% CI 13 56 40 56 38.7% 0.33 [0.20, 0.54] 3 45 13 45 17.0% 0.23 [0.07, 0.76] 17 34 25 30 44.3% 0.60 [0.41, 0.87] Risk ratio M-H, random, 95% CI 135 131 100.0% 0.40 [0.22, 0.73] Total events 33 78 Heterogeneity: 2 = 0.17; 2 = 5.99, df = 2 (P = 0.05); I 2 = 67% Test for overall effect: Z=3.02(P = 0.003) 0.001 0.1 1 10 1000 Figure 7: CDDP efficacy for FFA. SE (log [RR]) 0 0.2 0.4 0.6 0.8 1 0.01 0.1 1 10 100 RR Figure 8: Funnel plot of. 3.6. Adverse Events. No adverse events were recorded in any study, suggesting that CDDP may be safe. 4. Discussion Our data suggest that 270 540 mg CDDP may be used to treat DR as improvements in various indicators were noted. Of the 13 studies reviewed, the curative effect of CDDP for DR was showntobesuperiortocontrolsandthiswassignificantly different for vision improvements. This suggests that CDDP may delay vision loss and retard the progression of DR. The advantages of studies included definite diagnostic criteria and comparability for baseline data. But studies were of high risk methodological quality and samples were small. There was no multicenter trial or large samples for collaborative research. Only one study described the randomization method. Many participants were lost and not followed-up! There are five proposals: first, record in detail data of participants who were lost to follow-up or quit midway; second, record long followup and record important clinical outcomes after treatment, such as progression of retinopathy to PDR or sustained visual loss; third, methodological quality of clinical studies

Evidence-Based Complementary and Alternative Medicine 7 Participants (studies) follow-up 517 (7 studies) 2 6 months 293 (5 studies) 2-3 months 405 (6 studies) 2 6 months Table 3: Result of GRADE. Quality assessment Summary of findings Risk of Inconsistency Indirectness Imprecision Serious 1 inconsistency Serious 1 inconsistency Serious 1 Serious 3 Publication Overall quality of evidence Efficacy (critical outcome) strongly LOW 1,2 of, Study event rates (%) Relative effect With control group 115/252 (45.6%) Microaneurysms (better indicated by lower values) strongly LOW 1,2 of, Hemorrhage (better indicated by lower values) strongly LOW 1,2,3 of, inconsistency, Exudates (better indicated by lower values) With treatment group 214/265 (80.8%) (95% CI) RR 0.36 (0.28 to 0.46) 144 149 200 205 Anticipated absolute effects Time frame is 2 months to 6 months Risk with control group 456 per 1000 Risk difference with treatment group (95% CI) Study population 292 fewer per 1000 (from 246 fewer to 329 fewer) Moderate The mean s in the intervention groups were 4.32 lower (5.41 to 3.23 lower) The mean hemorrhage in the intervention groups was 0.40 lower (0.76 to 0.03 lower)

8 Evidence-Based Complementary and Alternative Medicine Participants (studies) follow-up 196 (2 studies) 2 6 months 272 (5 studies) 3months 266 (3 studies) 2 6 months Table 3: Continued. Quality assessment Summary of findings Risk of Inconsistency Indirectness Imprecision Serious 1 Serious 3 Serious 1 inconsistency Serious 1 inconsistency Publication strongly Overall quality of evidence LOW 1,2,3 of, inconsistency, Study event rates (%) Relative effect With control group Vision (better indicated by lower values) strongly strongly LOW 1,2 of, FFA LOW 1,2 of, With treatment group (95% CI) 98 98 134 138 78/131 (59.5%) 33/135 (24.4%) RR 0.4 (0.22 to 0.73) Anticipated absolute effects Time frame is 2 months to 6 months Risk with control group 595 per 1000 Risk difference with treatment group (95% CI) The mean exudates in the intervention groups were 0.09 lower (0.71 lower to 0.54 higher) The mean vision in the intervention groups was 0.12 lower (0.21 to 0.04 lower) Study population 357 fewer per 1000 (from 161 fewer to 464 fewer) Moderate 1 Assessed risk of according to six items:adequate sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data addressed, and being free of selective reporting; we assessed high risk according to quality assessment criteria; 2 check the of the systematic review that used the method of inverted funnel pattern analysis; the figure was asymmetrical, which showed that potential might influence the results of this paper; 3 95% confidence intervals of 14 studies overlap are poor.

Evidence-Based Complementary and Alternative Medicine 9 should use allocation concealment and complete outcome data should be addressed to prevent [32]; fourth, use the internationally accepted, uniform, and objective indicators of curativeeffect[33,34];fifth,forsearch,thenegativeresultof studies must be included. CDDP is compounded from extracts of S. miltiorrhiza, notoginseng (Panax notoginseng) and borneol. These three traditional Chinese medicines are widely used and have a long history of treatment in China. S. Miltiorrhiza and Panax notoginseng are used to treat cardiovascular conditions [35, 36]. S. miltiorrhiza contains a water soluble tanshinol which allegedly can decrease coagulation, increase fibrinolytic activity, inhibit thrombosis, platelet synthesis, andprostacyclinrelease,aswellasblockhydroxylradical production, prevent lipid peroxidation, and scavenge free radicals [37]. Mechanisms underlying CDDP may include free radical scavenging as S. miltiorrhiza ketone IIA can inhibit lipid peroxidation and reduce free radicals to protect endothelial diastolic function and vision and visual acuity was reportedly improved after treatment with CDDP [38, 39]. Improved microvascular structure was noted after CDDP treatment. The average thickness of micrangium decreased and diameters widened after CDDP for intake 3 months [18]. CDDP may improve microcirculation near the retina, opening capillaries, andrelievingtissueischemiaandhypoxiaandthiscanreduce DR symptoms or delay disease progression [40]. Endothelial dysfunction is prominent in hypercholesterolemic patients and it may contribute to DR by endothelial dysfunction [41]. CDDP may improve lipid metabolism. Hyperlipidemia damages the vascular wall and causes endothelial dysfunction, changing cell membrane structure and leading to microthrombi and ultimately causing DR. CDDP may then delay progression of DR by reducing blood lipids and improving blood flow [42, 43]. CDDP uses multiple sites, multiple pathways, and multitargets. It is characterized by convenient taking, rapid onset of action, and no obvious toxicity or adverse reactions. 5. Conclusion From this meta-analysis, we find that CDDP can be safe and efficacious retarding the progression of DR and delaying vision loss; thus it may be considered as an alternative way to treat DR. But the methodological quality was assessed to be of high risk and GRADE quality of evidence was low. Thereby, large-sample, high-quality randomized controlled clinical trials are warranted in the future. Conflicts of Interest Therearenoconflictsofinterest. Acknowledgments This paper is supported by the 2015 Traditional Chinese Medicine Scientific Research (no. 201507001-11). References [1] F. Kyari, A. Tafida, S. 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